Myoblast fusion is critical for myotube/myofiber formation, growth and maintenance. Our previous work has defined that myotube formation in mammals occurs in a two-stage process. Initially, myoblasts fuse with one another to form small nascent myotubes. A subset of nascent myotubes secretes the cytokine IL-4 leading to the recruitment and fusion of additional myoblasts and the formation of large mature myotubes. Little is known about the molecular mechanisms regulating this second phase of myoblast fusion. In several cell types IL-4 regulates expression of the mannose receptor (MR), a C-type lectin expressed on the surface of a number of cell types. Several roles have been ascribed to the MR. Importantly for this proposal the MR plays a role in cell adhesion and recognition and is implicated in macrophage fusion. Our preliminary data identify the MR as a novel regulator of the second phase of myoblast fusion and suggest that the MR functions downstream of IL-4 signaling. The overall goal of this proposal is to understand how the MR regulates the second phase of myoblast fusion. Towards this end we will analyze various aspects of myogenesis in MR null mice in vitro and in vivo. A set of 4 specific aims are proposed to analyze MR function and mechanism of action in vitro (Aim 1), analyze MR function during muscle regeneration in vivo (Aim 2), determine if the MR is associated with known pathways that regulate fusion (Aim 3) and identify its ligand (Aim 4). Our proposed studies will define a novel pathway in skeletal muscle for regulating myoblast fusion. Studies of the MR may lead to new strategies for manipulating myoblasts in disease, repair and aging and define novel therapeutic targets for enhancing muscle growth.